The present invention relates to treatments for substance dependence.
Substance dependence is a major problem, both for individuals suffering from it, and for society at large. At the individual level, the condition is characterized by a need for repeated, and often increasing doses of a substance. At the societal level, the condition is associated, with some substances, with increased levels of crime, including theft and crimes of violence, as sufferers seek to obtain supplies of the substance.
Individuals dependent on a substance find that they have to continue taking the substance, even though it produces harmful effects in them. They may become tolerant to the substance, which means that they need to take greatly increased amounts, for example ten times the amount they originally took, in order to achieve the same effect. Withdrawal of the substance brings about a variety of undesirable behavioral and physiological changes, including craving for the substance, anxiety and irritability.
In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, causing excitation of this receiving neuron.
L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, emotional states and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed "ionotropic." This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), .alpha.-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in cAMP formation, and changes in channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. Generally, these receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation. The metabotropic glutamate receptors (mGluR) have been pharmacologically divided into two subtypes. One group of receptors is positively coupled to phospholipase C, which causes hydrolysis of cellular phosphoinositides (PI). This first group are termed PI-linked metabotropic glutamate receptors. The second group of receptors is negatively coupled to adenyl cyclase, which prevents the forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP). Schoepp and Conn, Trends Pharmacol. Sci., 14, 13 (1993). Receptors within this second group are termed cAMP-linked metabotropic glutamate receptors.
There are many different substances on which individuals may become dependent. These include opiates, benzodiazepines, nicotine, cocaine and ethanol.
Nicotine dependence, which is induced through smoking, affects hundreds of millions of people around the world. For many, it leads to illness and premature death. Stopping smoking (smoking cessation) may evoke a range of symptoms in dependent individuals, including craving, depression, anxiety, difficulty in concentrating and weight gain.
A variety of treatments are available for smoking cessation, including counseling, hypnosis, aversion conditioning, relaxation training, acupuncture, and nicotine replacement therapy. However, in spite of the availability of these treatments, and the widespread knowledge of the harmful side effect of smoking, many smokers fail to give up smoking. There is therefore a need for new treatments for smoking cessation.
Benzodiazepine dependence, such as diazepam dependence, arises through the use of the benzodiazepines as pharmaceuticals to treat other disorders. The dependence-inducing properties of the benzodiazepines limits their therapeutic use. Withdrawal produces symptoms such as anxiety, irritability, insomnia and impaired concentration. There is therefore a need for new treatment for the treatment of benzodiazepine withdrawal.
Animal models for the treatment of nicotine and diazepam withdrawal have been described in Helton et al.; Psychopharmacology (1993), 113:205-210 and Rasmussen et al.; Neuroreport 5, 154-156 (1993). These models can be used to measure the ability of a test compound to inhibit the increased startle response in an animal (rat) following withdrawal of nicotine or diazepam.
It has now been found that a compound which is an agonist that acts selectively at negatively coupled cAMP-linked metabotropic glutamate receptors is capable of reducing startle response in rats following the cessation of chronic nicotine or diazepam exposure. It is believed that this finding portends that any agonist that acts at negatively coupled cAMP-linked metabotropic glutamate receptors will be useful for treating substance withdrawal, and indeed may be useful for providing protection against substance dependence.